ING117175: a Phase IIIb, Randomized, Open-label Study of the Safety and Efficacy of Dolutegravir or Efavirenz Each Administered With Two NRTIs in HIV-1-infected Antiretroviral Therapy-naïve Adults Starting Treatment for Rifampicin-sensitive Tuberculosis
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 113
- 试验地点
- 1
- 主要终点
- Percentage of Participants With Plasma Human Immunodeficiency Virus-1 Ribonucleic Acid (HIV-1 RNA) < 50 Copies/Milliliter at Week 48 in DTG Arm Using the Modified United States (US) Food and Drug Administration (FDA) Snapshot Algorithm
研究概览
简要总结
HIV/Tuberculosis (TB) co-infection have profound effects on the host's immune system. TB is the most common cause of death in patients with HIV worldwide. Rifamycins (such as rifampicin [RIF]) are an important component of TB therapy because of their unique activity. The problem is that most protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) used to treat HIV have significant drug-drug interactions with RIF that can lead to reduced concentrations of these agents with risk of treatment failure or resistance. The non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (EFV) does not present the same significant drug interactions with RIF. EFV-based HIV treatment was tested in patients concomitantly treated with RIF-containing TB therapy, demonstrating that their co-administration can be used safely and effectively. However, the side effect profile of EFV overlaps with the RIF-containing TB regimens and makes the management of treatment toxicities very complex. Integrase inhibitors (INI), such as dolutegravir (DTG), may offer an important alternative to EFV-based therapy in TB coinfected patients. A Phase I drug-drug interaction study was conducted in healthy, HIV-seronegative subjects, and showed that DTG at 50 mg twice daily given together with RIF was well-tolerated and resulted in DTG concentrations similar to those of DTG 50 mg given once daily alone, which is the recommended dose for INI-naive patients. Therefore, ART regimens using DTG 50 mg twice daily may represent a new treatment option for TB-infected patients who require concurrent treatment for HIV infection. This is a Phase III b, randomized, open-label study describing the efficacy and safety of DTG and EFV-containing ART regimens in HIV/TB co-infected patients. This study is designed to assess the antiviral activity of DTG or efavirenz (EFV) ART-containing regimens through 48 weeks. A total of approximately 115 +/-5% subjects will be randomly assigned in a 3:2 ratio to DTG (approximately 69 subjects) and EFV (approximately 46 subjects), respectively. This study will include a Screening Period, a Randomized Phase (Day 1 to 48 weeks plus a 4-week extension), and a DTG Open-label extension (OLE). During the DTG OLE, subjects will be supplied with DTG until it is locally approved and commercially available, the subject no longer derives clinical benefit, or the subject meets a protocol-defined reason for discontinuation, which ever comes first.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subject or the subject's legal representative is willing and able to understand and provide signed and dated written informed consent prior to Screening
- •Adult subject (at least 18 years of age) with plasma HIV-1 RNA>=1000 copies/ milliliter (mL) at Screening
- •CD4+ cell count is >= 50 cells/ cubic millimetre (mm^3) at Screening
- •HIV-1-infected, ART-naïve; (<=10 days of prior therapy with any antiretroviral drug following a diagnosis of HIV-1 infection)
- •A female subject may be eligible to enter and participate in the study if she: is of non-childbearing potential defined as either postmenopausal (12 months of spontaneous amenorrhea and >=45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy, or bilateral oophorectomy or, is of childbearing potential, with a negative pregnancy test at both Screening and Day 1, and agrees to use one of the following methods of contraception to avoid pregnancy
- •Complete abstinence from intercourse from 2 weeks prior to administration of IP, throughout the study, and for at least 2 weeks after discontinuation of all study medications
- •Double-barrier method (male condom/spermicide, male condom/diaphragm, diaphragm/spermicide)
- •Approved hormonal contraception plus a barrier method while receiving Rifampicin (RIF)-containing TB treatment for subjects randomly assigned to the DTG arm or approved hormonal contraception plus a barrier method for subjects randomly assigned to the EFV arm (regardless of RIF-containing TB treatment)
- •Any intrauterine device with published data showing that the expected failure rate is <1% per year
- •Male partner sterilization prior to the female subject's entry into the study and this male is the sole partner for that subject
- •Any other method with published data showing that the expected failure rate is <1% per year
- •Any contraception method must be used consistently, in accordance with the approved product label and for at least 2 weeks after discontinuation of study drug. A childbearing potential female subject who starts the study using complete abstinence as her contraceptive method and decides to become sexually active must use the double barrier method either as a bridge to an approved hormonal contraception (if possible) or as a method of choice to be maintained from that moment onwards
- •All subjects participating in the study should be counseled on safer sexual practices including the use of effective barrier methods
- •New diagnosis of pulmonary, pleural, or Lymph node (LN) TB based on identification of Mycobacterium tuberculosis using culture methods or validated nucleic acid amplification test on sputum or on samples collected by needle aspirate of pleural fluid or an affected LN
- •RIF sensitivity of Mycobacterium tuberculosis either by culture or validated nucleic acid amplification test
- •RIF-containing first-line TB treatment or an alternate RIF-containing TB treatment started up to a maximum of 8 weeks before randomization and no later than the screening date
- •Karnofsky score >=70% before randomization
排除标准
- •Any previous TB treatment (not including treatment for latent disease)
- •Evidence of RIF resistance of Mycobacterium tuberculosis either by culture or validated nucleic acid amplification test
- •Expected requirement for TB treatment >9 months
- •Concomitant disorders or conditions for which isoniazid, RIF, pyrazinamide, or ethambutol are contraindicated
- •Central nervous system, miliary, or pericardial TB
- •Women who are pregnant or breastfeeding
- •Any evidence of an active Acquired immunodeficiency syndrome (AIDS)-defining disease (Centers for Disease Control and Prevention, Category C). Exceptions include TB, cutaneous Kaposi's sarcoma not requiring systemic therapy, and historic CD4+ cell counts of <200 cells/mm^3
- •Subjects with moderate to severe hepatic impairment (Class B or C) as determined by Child-Pugh classification unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), cirrhosis, or known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
- •Subjects positive for hepatitis B surface antigen (HBsAg) at screening
- •Anticipated need for hepatitis C virus (HCV) therapy during the Randomized Phase of the study
- •History or presence of allergy or intolerance to the study drugs or their components or drugs of their class
- •Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, resected, non-invasive cutaneous squamous cell carcinoma, or cervical intraepithelial neoplasia; other localized malignancies require agreement between the investigator and the study medical monitor for inclusion of the subject
- •Subjects who, in the investigator's judgment, pose a significant suicidality risk. Recent history of suicidal behavior and/or suicidal ideation may be considered as evidence of serious suicide risk
- •Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening
- •Treatment with any of the following agents within 28 days of Screening: radiation therapy, cytotoxic chemotherapeutic agents, any immunomodulators that alter immune response
- •Treatment with any agent, other than licensed ART as allowed above with documented activity against HIV-1 in vitro/vivo within 28 days of first dose of IP
- •Exposure to an experimental drug or experimental vaccine within either 28 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is longer, prior to the first dose of IP
- •Any evidence of primary viral resistance to Nucleoside reverse transcriptase inhibitor (NRTIs), Non-nucleoside reverse transcriptase inhibitor (NNRTIs), or Protease inhibitor (PIs) based on the presence of any major resistance-associated mutation (according to the International AIDS Society Update of the Drug Resistant Mutations in HIV-1 ) in the Screening result or, if known, any historical resistance test result. Note: Retests of Screening genotypes are not allowed
- •Any verified Grade 4 laboratory abnormality
- •Any acute laboratory abnormality at Screening, which, in the opinion of the investigator, would preclude the subject's participation in the study of an investigational compound
- •Alanine aminotransferase >=2 × upper limit of normal
- •Hemoglobin <=7.4 grams per deciliter;
- •Platelet count <50000/mm^3
研究组 & 干预措施
Dolutegravir
Twice-daily DTG 50 mg plus dual NRTI during RIF-containing TB treatment (isoniazid, RIF, pyrazinamide and ethambutol standard doses by the NTP under program conditions or acceptable alternative RIF-containing regimens) and for 2 weeks following discontinuation of TB treatment, then once-daily DTG 50 mg with the same NRTI through Week 52
干预措施: DTG 50 mg (Drug)
Efavirenz
Once-daily EFV 600 mg plus dual NRTI through Week 52 along with TB treatment including isoniazid, RIF, pyrazinamide and ethambutol standard doses by the NTP under program conditions.
干预措施: EFV 600 mg (Drug)
结局指标
主要结局
Percentage of Participants With Plasma Human Immunodeficiency Virus-1 Ribonucleic Acid (HIV-1 RNA) < 50 Copies/Milliliter at Week 48 in DTG Arm Using the Modified United States (US) Food and Drug Administration (FDA) Snapshot Algorithm
时间窗: Week 48
Plasma samples were collected for quantitative analysis of HIV-1 RNA. The percentage of participants with plasma HIV-1 RNA \<50 copies/milliliter was assessed at Week 48 using the snapshot algorithm in the DTG arm. Response was assessed using a modified FDA Snapshot algorithm in which participants were not penalized for any single protocol allowed background therapy substitution even if occurs after the first trial visit. In this approach participants with HIV-1 RNA \>=50 copies/milliliter are considered as non-responders. Participants without HIV-1 RNA data at Week 48 (due to missing data or discontinuation of investigational product \[IP\] prior to visit window) are also considered as non-responders, as well as participants with anti-retroviral (ART) substitutions were not permitted. Study drug (i.e. DTG or EFV) was not allowed to be substituted.
次要结局
- Number of Participants With Maximum Post-Baseline-emergent Hematology Toxicities- Randomized Phase(Up to Week 52)
- Number of Participants With Maximum Post-Baseline-emergent Hematology Toxicities - Randomized Phase + OLE Phase(Up to Week 252)
- Percent Change From Baseline in the Fasting Lipid Profile at Week 24 and Week 48(Baseline (Day 1), Week 24 and Week 48)
- Change From Baseline in the Fasting Lipid Profile for Total Cholesterol/HDL Ratio at Week 24 and Week 48(Baseline (Day 1), Week 24 and Week 48)
- Percentage of Participants Who Permanently Discontinued Study Treatment Due to AEs - Randomized Phase(Up to Week 52)
- Percentage of Participants Without Confirmed Virologic Withdrawal and Without Discontinuation Due to Treatment-related Reasons at Week 24 and Week 48(Week 24 and Week 48)
- Percentage of Participants With Plasma HIV-1 RNA <50 Copies/Milliliter at Week 24 in Both EFV and DTG Arms Using the Modified Snapshot Algorithm(Week 24)
- Percentage of Participants With Plasma HIV-1 RNA <50 Copies/Milliliter at Week 48 in EFV Arm Using the Modified Snapshot Algorithm(Week 48)
- Change From Baseline in Cluster of Differentiation 4 (CD4+) Counts at Week 24 and Week 48(Baseline (Day 1), Week 24 and Week 48)
- Number of Participants With Serious Adverse Event (SAE) and Common (>=5%) Non-serious AE (Non-SAE) - Randomized Phase(Up to Week 52)
- Number of Participants With SAE and Common (>=5%) Non-SAE - OLE Phase(Week 52 to Week 252)
- Number of Participants With Maximum Post-Baseline-emergent Chemistry Toxicities - Randomized Phase(Up to Week 52)
- Number of Participants With Maximum Post-Baseline-emergent Chemistry Toxicities- Randomized Phase + OLE Phase(Up to Week 252)
- Percentage of Participants Who Permanently Discontinued Study Treatment Due to AEs - OLE Phase(Week 52 to Week 252)
- Number of Participants With Tuberculosis (TB) Associated (Assoc.) Immune Reconstitution Inflammatory Syndrome (IRIS)(Up to Week 12)
- Number of Participants With Treatment-emergent Genotypic Resistance(Up to Week 52)
- Number of Participants With Treatment-emergent Phenotypic Resistance(Up to Week 52)